In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluRs"" are known and of these some even have sub-types. On the basis of structural parameters, the different second messager signalling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I;
mGluR2 and mGluR3 belong to group II; and
mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The present invention is concerned with carbamic acid ester derivatives of the formula: 
wherein
R1 signifies hydrogen or lower alkyl;
R2, R2xe2x80x2 signify, independently from each other, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
X signifies O, S or two hydrogen atoms not forming a bridge;
A1/A2 signify, independently from each other, phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms;
B is a group of formula: 
wherein
R3 signifies lower alkyl, lower alkenyl, lower alkinyl, benzyl, lower alkyl-cycloalkyl, lower alkyl-cyano, lower alkyl-pyridinyl, lower alkyl-lower alkoxy-phenyl, lower alkyl-phenyl, which is optionally substituted by lower alkoxy, or phenyl, which is optionally substituted by lower alkoxy, or lower alkyl-thienyl, cycloalkyl, lower alkyl-trifluoromethyl or lower alkyl-morpholinyl;
Y signifies xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or a bond;
Z signifies xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
or B is a 5-membered heterocyclic group of formulas: 
wherein
R4 and R5 signifies hydrogen, lower alkyl, lower alkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with the proviso that at least one of R4 or R5 has to be hydrogen; as well as with their pharmaceutically acceptable salts.
In particular, the invention relates to compounds of the following structures: 
wherein the definition of substituents is given above.
These compounds and their salts are novel and are distinguished by valuable therapeutic properties.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor modulators, acting as antagonists or agonists.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
Preferred compounds of formula I in the scope of the present invention are those, in which A signifies phenyl, X signifies 2 hydrogen atoms not forming a bridge and B signifies the group: 
wherein Z is O and R3 and Y are described above.
The following are examples of such compounds:
diphenylacetyl-carbamic acid butyl ester,
diphenylacetyl-carbamic acid ethyl ester or
diphenylacetyl-carbamic acid pent-4-ynyl ester.
Compounds of formula I, wherein A signifies phenyl, X signifies xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and B signifies the group: 
are further preferred, wherein Z is O and R3 and Y are described above.
Examples of such compounds are:
(9H-xanthene-9-carbonyl)-carbamic acid ethyl ester,
(9H-xanthene-9-carbonyl)-carbamic acid butyl ester or
(9H-thioxanthene-9-carbonyl)-carbamic acid butyl ester.
Preferred compounds of formula I in the scope of the present invention are those, in which A signifies phenyl, X signifies 2 hydrogen atoms not forming a bridge and B signifies a heterocyclic group of the formulas: 
wherein R4 and R5 have the significances given above.
Examples of such compounds are:
N-(5-ethyl-oxazol-2-yl)-2,2-diphenyl-acetamide,
N-(5-methyl-oxazol-2-yl)-2,2-diphenyl-acetamide,
2,2-diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)-acetamide,
N-[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenyl-acetamide,
N-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide,
N-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide or
N-(5-methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenyl-acetamide.
Preferred are further compounds of formula I, in which A signifies phenyl, X signifies xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and B signifies a heterocyclic group of the formulas: 
for example the following compounds:
9H-xanthene-9-carboxylic acid oxazol-2-yl-amide,
9H-xanthene-9-carboxylic acid (5-propyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-ethyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-methyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-propyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (4-methyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (3-methyl-[1,2,4]oxadiazol-5-yl)-amide,
9H-Xanthene-9-carboxylic acid (5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-Xanthene-9-carboxylic acid (5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-amide or
9H-xanthene-9-carboxylic acid (5-methyl-[1,2,4]oxadiazol-3-yl)-amide.
The invention embraces all stereoisomeric forms in addition to the racemates.
The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d embraces fluorine, chlorine, bromine and iodine.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by processes, which comprises
reacting a compound of the formula: 
with a compound of the formula: 
to a compound of formula: 
wherein the substituents have the significances given above, or
b) reacting a compound of formula: 
with a compound of the formula: 
to a compound of formula: 
in which G is a suitable leaving group, such as Cl, Br or acyloxy, or a carbonyl chloride equivalent such as a carbonyl-pyrazolide, carbonyl imidazole, carbonyl benzotriazole, carbonyloxysuccinimide, or activated esters such as p-nitrophenylester, pentachlorophenylester and the like, and the other substituents have the significances given above,
c) or reacting a compound of formula: 
with a compound of the formula: 
to a compound of formula: 
or
d) reacting a compound of formula: 
with a compound of the formula: 
to a compound of formula: 
wherein the substituents have the significances set forth above, or
e) reacting a compound of formula: 
with a heterocyclic compound of formula
Bxe2x80x94NH2xe2x80x83xe2x80x83IX
to give a compound of formula: 
wherein B is a 5-membered heterocycle of the formulas: 
and wherein the remaining substituents have the significances given above, and, if desired, converting a functional group in a compound of formula I into another functional group and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
In accordance with process variant a) to a compound of formula III, for example an alcohol (1-butanol, benzyl alkohol, allyl alkohol, isopropyl-alkohol) in dichloromethane is added a compound of formula II, for example diphenylacetyl isocyanate and the mixture is stirred at room temperature.
Compounds of formula IA may be prepared in accordance with process variant b). A compound of formula V, for example a corresponding urethane or carbamic acid alkyl ester, is reacting with a compound of formula IV, for example with 9H-xanthene-9-carbonyl chloride or bromide, or with an acyloxy derivative of formula IV, or with a carbonyl chloride equivalent of formula IV, which compounds contain a carbonyl-pyrazolide group, a carbonyl imidazole group, a carbonyl benzotriazole group, a carbonyloxysuccinimide group or an activated ester such as p-nitrophenylester, pentachlorophenylester and the like. This reaction is carried out in a solvent, such as pyridine, at room temperature by methods known in the art.
Furthermore, compounds of formula IA-1 and IA may be prepared in accordance with process variant c) and d), wherein a compound of formula VI is reacting with a compound of formula VII or VIII. This reaction is carried out similar to those, described for process variant b). Compounds of formula IB may be prepared by a reaction of a heterocyclic compound of formula IX with a compound of formula IV in the presence of N,N-dimethylamino pyridine at a temperature of 0xc2x0 C. The preferred solvent is methylene chloride.
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation or pharmaceutically acceptable salts of acidic compounds.
Scheme 1 gives an overview of the manufacture of the compounds of formula IA. The manufacture of representative compounds of formula I is described in detail in examples 1-30, 32 and 34-43. Scheme 2 describes the process of manufacture of compounds of formula IB, which process is described in more detail in examples 31, 33 and 44-69.
The substituents have the significances given earlier. 
wherein B is a 5-membered heterocyclic compound of formulas: 
and the remaining definitions of substituents are given above.
The starting materials used in schemes 1 and 2 are known compounds or may be prepared by methods known per se.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor agonists and/or antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer""s disease, cognitive diorders and memory deficits, as well as acute and chronic pain. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Alzheimer""s disease, Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The compounds of the present invention are group I mGlu receptor agonists and/or antagonists. For example, it has been shown that the compounds of examples 1-22 and 30-69 show agonistic activities and those of examples 23-29 are antagonists. The compounds show activities, as measured in the assay described below, of 50 xcexcM or less, typically 1 xcexcM or less, and ideally of 0.5 xcexcM or less.
In the table below are shown some specific activity-data:
cDNA encoding rat mGlu 1a receptor obtained from Prof. S. Nakanishi (Kyoto, Japan) was transiently transfected into EBNA cells using a procedure described by Schlaeger et al, New Dev. New Appl. Anim. Cell Techn., Proc. ESACT Meet., 15, (1998), 105-112 and 117-120. [Ca2+]i measurements were performed on mGlu 1a transfected EBNA cells after incubation of the cells with Fluo-3 AM (0.5 xcexcM final concentration) for 1 hour at 37xc2x0 C. followed by 4 washes with assay buffer (DMEM supplemented with Hank""s salt and 20 mM HEPES. [Ca2+]i measurements were done using a fluorometric imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, Calif., USA). When compounds were evaluated as antagonists they were tested against 10 xcexcM glutamate as agonist.
The inhibition (antagonists) or activation (agonists) curves were fitted with a four parameter logistic equation giving EC50, and Hill coefficient using the iterative non linear curve fitting software Origin (Microcal Software Inc., Northampton, Mass., USA).
The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of medicaments, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind, is also an object of the invention.